Background: Sarcomatoid renal cell carcinomas (SRCC) are aggressive tumors usually diagnosed at advanced stage and represent 5-8% of RCC. Sarcomatoid differentiation occurs through the process of epithelial-mesenchymal transition (EMT), in which transcriptional factor ZEB1, a repressor of E-cadherin (E-cad), represents an important inducer. We analyzed morphologic features and immunohistochemical (IHC) profile of spindle cell (SC) and carcinomatous (CC) components of SRCC, with emphasis on EMT-related markers.Design: We reviewed 20 cases of SRCC: 10 clear cell (CCRCC), 6 chromophobe (ChRCC) and 4 papillary (PRCC). We performed IHC staining for epithelial [E-cad, N-cadherin (N-cad), b-catenin] and mesenchymal [ZEB1, SPARC] markers. Staining was evaluated as sum of intensity (0-3) and extent (0-3) and a final score >3 corresponded to high expression. We classified the SC as type-1 (sarcoma-like) and type-2 (early epithelial spindling) according to growth pattern, cellularity, nuclear/cytoplasmic ratio, pleomorphism, and mitotic rate/10HPF (MR) and correlated it with pattern of staining, tumor size, stage, metastatic disease and outcome.Results: 13 (65%) SRCC (4 CCRCC, 3 PRCC, 6 ChRCC) were classified as type-1 and 7 (35%) as type-2 (6 CCRCC, 1 PRCC). High expression of epithelial markers was found in most CC with no differences between types. Epithelial markers were less expressed in SC. ZEB1 and SPARC were highly expressed in SC but not in CC. 92% of type-1 SRCC showed high expression of ZEB1 in SC, compared to 29% of type-2 (p=0.007). Type-1 SRCC were significantly larger (p=0.043), had significantly higher % of SC (p=0.031), presented at higher stage and had higher MR (p›0.05). 75% type-1 and 86% of type-2 SRCC presented with or developed visceral or bone metastases; 61% of type-1 died of disease (DOD) vs. 29% of type-2.

% of SRCC with high expression of IHC markers

E-cad

N-cad

β-catenin

ZEB1

SPARC

CC

Type-1

85

100

100

0

0

Type-2

71

100

100

14

29

SC

Type-1

0

54

46

92

100

Type-2

14

86

57

29

100

Pathological and clinical parameters

Tumor size, median

SC MR, median

%SC, median

Stage ≥pT3

Visceral/bone metastases

NED, AWD, DOD

Type-1

10.7

12

70

77%

75%

15%, 23%, 61%

Type-2

6.5

8

30

71%

86%

14%, 57%, 29%

Conclusions: SC of SRCC showed low expression of epithelial and high expression of mesenchymal markers. 35% of SRCC showed an early epithelial spindling SC compared to sarcoma-like pattern. Spindle cell proliferations classified as SRCC are histologically heterogeneous, which may have important clinical implications. ZEB1 may be a useful tool in discerning different types of SC in SRCC.Category: Genitourinary (including renal tumors)